Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids.[1] Many of them possess significant physiological activity with psychological effects. For example, the amino acidtryptophan is the biochemical precursor of indole alkaloids.[2]

Consumption of rye and related cereals contaminated with the fungusClaviceps purpurea causes ergot poisoning and ergotism in humans and other mammals. The relationship between ergot and ergotism was established only in 1717, and the alkaloid ergotamine, one of the main active ingredients of ergot, was isolated in 1918.[5]

There are also purely structural classifications based on the presence of carbazole, β-carboline or other units in the carbon skeleton of the alkaloid molecule.[10] Some 200 dimeric indole alkaloids are known with two indole groups.[11]

The prevalence of β-carboline alkaloids is associated with the ease of forming the β-carboline core from tryptamine in the intramolecular Mannich reaction. Simple (non-isoprenoid) β-carboline derivatives include harmine, harmaline, harmane[17] and a slightly more complex structure of canthinone.[18] Harmaline was first isolated in 1841 by Goegel[19] and harmine in 1847 by Fritsche.[20][21][22]

Pyrolo-indole alkaloids form a relatively small group of tryptamine derivatives. They are produced by methylation of indole nucleus at position 3 and the subsequent nucleophilic addition at the carbon atom in positions 2 with the closure of the ethylamino group into a ring. A typical representative of this group is physostigmine,[23] which was isolated by Jobst and Hesse in 1864.[24][25]

Ergot alkaloids are a class of hemiterpenoid indole alkaloids related to lysergic acid, which, in turn, is formed in a multistage reactions involving tryptophan and DMAPP. Many ergot alkaloids are amides of lysergic acid. The simplest such amide is ergine, and more complex can be distinguished into the following groups:[26][27]

Ergotinine, discovered in 1875, and ergotoxine (1906) were subsequently proven to be a mixture of several alkaloids. In pure form, the first ergot alkaloids, ergotamine and its isomer ergotaminine were isolated by Arthur Stoll in 1918.[27]

Most monoterpenoid alkaloids included a C9 or C10 fragment originating from the secologanin. Depending on the structure of this fragment, these alkaloids belong to Corynanthe, Iboga and Aspidosperma classes named by a typical genus or species of the plant which contain such alkaloids. The monoterpenoid part of their carbon skeletons are illustrated below on the example of alkaloids ajmalicine and catarantine. The circled carbon atoms are missing in the alkaloids which contain the C9 fragment instead of C10.[15]

There is also a small group of alkaloids present in the plant Aristotelia – about 30 compounds, the most important of which is peduncularine – which contain a monoterpenoid C10 part originating not from secologanin.[31]

Apart from bisindole alkaloids, dimeric alkaloids exist which are formed via dimerization of the indole monomer with another type of alkaloid. An example is tubulosine consisting of indole and isoquinoline fragments.[33]

Biosynthesis of β-carboline alkaloids occurs through the formation of Schiff base from tryptamine and aldehyde (or keto acid) and subsequent intramolecular Mannich reaction, where the C(2) carbon atom of indole serves as a nucleophile. Then, the aromaticity is restored via the loss of a proton at the C(2) atom. The resulting tetrahydro-β-carboline skeleton then gradually oxidizes to dihydro-β-carboline and β-carboline. In the formation of simple β-carboline alkaloids, such as harmine and harmaline, pyruvic acid acts as the keto acid. In the synthesis of monoterpenoid indole alkaloids, secologanin plays the role of the aldehyde. Pirroloindole alkaloids are synthesized in living organisms in a similar way.[40]

Biosynthesis of ergot alkaloids begins with the alkylation of tryptophan by dimethylallyl pyrophosphate (DMAPP), where the carbon atom C(4) in the indole nucleus plays the role of the nucleophile. The resulting 4-dimetilallil-L-tryptophan undergoes N-methylation. Further products of biosynthesis are chanoclavine-I and agroclavine – the latter is hydroxylated to elymoclavine, which in turn oxidizes into paspalic acid. In the process of allyl rearrangement, paspalic acid is converted to lysergic acid.[41]

Biosynthesis of monoterpenoid indole alkaloids begins with the Mannich reaction of tryptamine and secologanin; it yields strictosidine which is converted to 4,21-dehydrogeissoschizine. Then, the biosynthesis of most alkaloids containing the unperturbed monoterpenoid part (Corynanthe type) proceeds through cyclization with the formation of cathenamine and subsequent reduction to ajmalicine in the presence of nicotinamide adenine dinucleotide phosphate (NADPH). In the biosynthesis of other alkaloids, 4,21-dehydrogeissoschizine first converts into preaquamycin (an alkaloid of subtype strychnos, type Corynanthe) which gives rise to other alkaloids of subtype strychnos and of the types Iboga and Aspidosperma. Bisindole alkaloids vinblastine and vincristine are produced in the reaction involving catarantine (alkaloid of type Iboga) and vindolin (type Aspidosperma).[29][42]

Ergolines, such as lysergic acid, include structural elements of both tryptamine and phenylethylamine and thus act on the whole group of the 5-HT receptors, adrenoceptors (mostly of type α) and dopamine receptors (mostly type D2).[48][49] So ergotamine is a partial agonist of α-adrenergic and 5-HT2 receptors, and thus narrows blood vessels and stimulates constriction of the uterus. Dihydroergotamine is more selective to α-adrenergic receptors and has a weaker effect on serotonin receptors. Ergometrine is an agonist of α-adrenergic, 5-HT2 and partly D2 receptors.[49][50] Compared with other ergot alkaloids, ergometrine has a greater selectivity in stimulating the uterus.[50]LSD, a semi-synthetic psychedelic ergoline, is an agonist of 5-HT2A, 5-HT1A and to a lesser extent D2 receptors and has a powerful psychedelic effect.[51][52]

Some monoterpenoid indole alkaloids also interact with adrenoceptors. For example, ajmalicine is a selective antagonist of α1-adrenergic receptors and therefore has antihypertensive action.[53][54]Yohimbine is more selective to α2 adrenoceptor;[54] by blocking presynaptic α2-adrenoceptors, it increases the release of norepinephrine thereby raising the blood pressure. Yohimbine was used for the treatment of erectile dysfunction in men until emergence of more efficient drugs.[55]

Later, the plants were joined by pure preparations of indole alkaloids. Reserpine was the second (after chlorpromazine) antipsychotic drug; however, it showed relatively weak action and strong side effects, and is not used for this purpose any longer.[62] Instead, it is prescribed as an antihypertensive drug, often in combination with other substances.[63]

Animal studies have shown that ibogaine has a potential in treating heroin, cocaine, and alcohol addictions, which is associated with the ibogaine antagonism to NMDA-receptors. Medical use of ibogaine is hindered by its legal status, as it is banned in many countries as a powerful psychedelic drug with dangerous implications of overdose. However, illegal network in Europe and United States provide ibogaine for treating drug addiction.[68][69]